Existing non-surgical cancer therapies and treatments rely on the use of compounds or radiation doses that are non-specific for the tumor cells and are highly toxic to humans. The treatments generally involve near-lethal doses that are destructive to all cells, but are particularly effective against rapidly proliferating tumor cells. The result of the these treatments is that there are severe side-effects to most cancer treatments. In addition, their efficacy is limited by their non-specificity. The design of rational drugs or treatments that specifically target malignantly transformed cells would dramatically improve the efficacy and reduce the harmful consequences of cancer therapeutics. Treatments that specifically target defective processes in tumor cells, such as those regulatory processes debilitated by mutations in oncogenes and tumor suppressor genes, are the most likely to be highly effective.
The p53 tumor suppressor is among the most frequently mutated gene known in human cancers. It has therefore become one of the most desirable molecular targets for clinical intervention in cancer. The p53 protein is critically involved in the integration of signals regulating cell cycle progression with opposing signals that activate programmed cell death (PCD or apoptosis) (Levine, A., Cell, Vol.88: 323–331 (1997) and L. J. Ko & C. Prives, Genes & Dev. Vol. 10, 1054 (1996)). Moreover, the activity of p53 often determines whether a cell continues to proliferate or undergoes PCD. The p53 protein binds to conserved sequences of DNA that control the activation of numerous genes required for cell cycle control as well as PCD. For example, in response to ionizing radiation p53 can transactivate the cyclin-dependent kinase inhibitor p21 (El Deiry W. S., et al., Cancer Research, Vol.54: 1169–1174(1994); Namba, H., et al., Cancer Research, Vol.55: 2075–2080 (1995); Chin et al., Oncogene, Vol. 15: 87–99(1997) or the bax gene (Miyashita, T. & Reed, J. C. Cell, Vol.80: 293–299 (1995)), leading to cell cycle arrest or apoptosis, respectively. In this regard, p53 acts to monitor the integrity of the genome (Levine, A., supra.) and in so doing, effectively prevents the formation of tumors which might otherwise arise as a result of genomic instability.
In addition to binding DNA and regulating gene expression, p53 also interacts with numerous proteins in the nucleus and the cytoplasm. Many of these interactions are believed to regulate cell death and the cellular responses to only a few of these interactions are beginning to be understood. However, little is known about how p53 is regulated or which aspects of its regulation determine whether cell cycle progression is halted and/or PCD is activated. Moreover, nothing is known about the existence of parallel pathways, which might function in cooperation with p53 in the context of tumor suppression.
Studies of p53 function in vertebrates are complicated by the existence of multiple p53-like genes, which may act redundantly (M. A. E. Lohrum, & K. H. Vousden, Cell Death Diff. Vol. 6, 1162 (1999)). Analysis of the mechanisms through which p53-like proteins integrate response to stress and damage in vivo has also been limited by the absence of a genetic system. To investigate the role of p53 in DNA damage and stress-response in a genetically accessible system, we have characterized the function of the p53 homolog in the nematode C. elegans. 
Methods that reactivate p53 function in tumors carrying mutations in this gene, or methods that bypass the requirement for its important role in suppressing tumor formation, are likely to prove effective for eliminating tumors. The majority of information on this molecule has been obtained from studies in cultured tumor cell lines or using mice where genetic redundancy complicates interpretation of its function. Most importantly, it has not heretofore been possible to analyze p53 function using the powerful approaches of genetics, nor is it practical to use an intact animal to perform high-throughput screens for agents that enhance the efficacy of p53.
It is therefore highly desirable to study the function of p53 and methods that activate the anti-tumor function of the p53 pathway in a simpler organism in which genetic redundancy is not a complicating factor, and in which molecules that facilitate p53 action can be readily identified.
The nematode Caenorhabditis elegans is a small free-living nematode which grows easily and reproduces rapidly in the laboratory. The anatomy of C. elegans is relatively simple and extremely well-known, and its developmental cell lineage is highly reproducible and completely determined. There are two sexes: hermaphrodites that produce both eggs and sperm and are capable of self fertilization and males that produce sperm and can productively mate with the hermaphrodites. The self fertilizing mode of reproduction greatly facilitates the isolation and analysis of genetic mutations and C. elegans has developed into a most powerful animal model system, For example, the discovery that an initiator of apoptosis in this animal is a caspase enzyme led to the development of caspase inhibitors (Garcia-Calvo, M., et al., J. Biol. Chem., Vol.273: 32608–32613 (1998) and Rasper, D. M., et al., Cell Death and Differentiation, Vol.5: 271–288 (1998)). Caspase inhibitors are currently being used in clinical trials in humans in an effort to block neurodegenerative diseases, amply demonstrating that gene discovery in C. elegans can lead directly to novel medical therapeutics. Thus, the strong conservation of structure and function in C. elegans genes makes this organism a remarkably powerful model system for discovering novel molecules in the p53 pathway which may prove to be relevant targets for clinical intervention in humans and/or may lead to novel diagnostics and prognostics.